Multipurpose Prevention Technology (MPT)
Manufacturing Issues
Live Webinar
Featuring:
Dr. Joseph Romano (NWJ Group LLC)
Dr. Kenneth Stockholm (Q Pharma)
Dr. Robert Russell (RJR Consulting)
Multipurpose Prevention Technology
(MPT) Manufacturing Issues
26 September 2014 Live Webinar Hosted by CAMI Health
MPT Manufacturing Issues
Live Webinar – 26 September 2014
Dr. Joseph Romano
President of NWJ Group LLC
Introductory Remarks
MPT Manufacturing Issues Live Webinar – 26 September 2014
Background for Today’s Webinar
Quality elements of new products are critical
from the earliest stages of development
Early stage design decisions must be informed
by later stage quality requirements and
consequences
Inadequacies in the CMC package can
prevent product approval despite clinical
demonstration of safety and efficacy
Are MPT funders and developers adequately
informed of CMC requirements and risk?
MPT Manufacturing Issues Live Webinar – 26 September 2014
Today’s CMC Topics
Consideration of late stage manufacturing
requirements in early stage product design
Kenneth Stockholm
Q Pharma
A review of the FDA guidance for Scale Up
and Post-Approval Changes (SUPAC)
Robert Russell
RJR Consulting
MPT Manufacturing Issues
Live Webinar – 26 September 2014
Mr. Kenneth Stokholm
Managing Director at QPharma
MPT Manufacturing - The CMO Perspectives
MPT Manufacturing Issues Live Webinar – 26 September 2014
Agenda
Introduction
CMO perspectives
Challenges
Our involvement across the development phases
Design path and space
Cost of goods
Components and drivers
Scale up
7
MPT Manufacturing Issues Live Webinar – 26 September 2014
Contract Development and Manufacturing Organisation Solid pharmaceutical history since 1975 Private company
Employs 134 people
Turn-over 26 million USD (167 MSEK) in 2013 AAA Financial rating
Compliance with US FDA & EMEA regulations
Competencies Solid dosage forms Vaginal rings, IUD’s and implants
Who we are
8
MPT Manufacturing Issues Live Webinar – 26 September 2014
The common ground
Formulations
Indications
HRT
STD, HIV
Infertility
Contraception
Urinary incontinence
Reproductive cancers
Oncology
Pain
Clients
9
MPT Manufacturing Issues Live Webinar – 26 September 2014
Challenges
Split between pharmaceutical clients and non profit
organizations (and their donors)
Understanding pharmaceutical development
Design path and space
Clinical trials
Cost of goods
Defining finished product properties in early
development
Early involvement of CMO
Regulatory approval
Robust, cost effective process
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MPT Manufacturing Issues Live Webinar – 26 September 2014
Feasibility studies (Proof of Concept)
Design development
Clinical trial supplies I-II, based on lab scale
Scale up of manufacturing process (QbD and DoE)
Clinical supplies III, based on pilot/commercial scale
Launch
Post approval changes (SUPAC)
CMO involvement across phases
Feasibility Development Clinical Trials
I- II Scaling up
Clinical Trials III
Launch
11
MPT Manufacturing Issues Live Webinar – 26 September 2014
Development
Feasibility
Process development
Phase I-II Clinical
Phase III Clinical
Resources Do process
development
properly before
Clinical Phase III trials
GMP work
space
GMP
equipment
GMP work space
Production
equipment
QbD
Pilot equipment IVIVC
Time (months) 6-12 12-24 12-36 24-60
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MPT Manufacturing Issues Live Webinar – 26 September 2014
Polymeric formulation (IVR, IUD, Implant)
Design (reservoir, matrix)
Release profile (rate, duration, burst)
Raw materials (Silicone type, thermoplastic (EVA, PU, other))
Cross linking
Curing system
API (grade, particle size, SSA, etc.)
Manufacturing process (mixing, extrusion/injection molding)
Scale (laboratory, pilot, commercial)
Cost of goods
IP
Design parameters 1
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MPT Manufacturing Issues Live Webinar – 26 September 2014
Duration – short or long term? Formulation Tablets, gels Polymeric formulation (IVR, IUD, Implant) Release profile, rate – burst? Design Reservoir Matrix
MPT (combination)? Design/manufacturing process 1 Extrusion Cost of goods? Raw materials Silicone, API IP protection / license opportunity? Design/manufacturing process 2 Membrane, enhancer
Which development process? Scale
Design path 2
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MPT Manufacturing Issues Live Webinar – 26 September 2014
Design space 3
Polymeric formulation
Release profile
MPT
Silicone, API
Final Design Space
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MPT Manufacturing Issues Live Webinar – 26 September 2014
Cost of Goods components 1
Direct material
Direct labor
Production
Quality
Overhead
Direct Material12%
Direct Labour27%
Production28%
Quality9%
Overhead24%
Cost components
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MPT Manufacturing Issues Live Webinar – 26 September 2014
Cost of Goods dependencies 2
Manufacturing scale (Laboratory, pilot and
commercial)
Batch size
Direct costs
Fixed costs
Automation versus labor
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MPT Manufacturing Issues Live Webinar – 26 September 2014
Cost of Goods comparison 3
Price development
through clinical supply
phases into commercial
supply
At larger volumes, fixed
costs will be insignificant
Price per unit, per day of
treatment or total cost
of treatment?
1000
300
10050 10 3
0
200
400
600
800
1000
1200
1400
100 1K 10K 100K 1M 10MU
SD p
er
rin
g
Rings per year
Cost comparison
18
MPT Manufacturing Issues Live Webinar – 26 September 2014
Conclusions
Early CMO involvement will secure
Right priority of the final product properties
Scalability
Less regulatory impact
Robust, cost effective commercial process
Shorter time to market
19
MPT Manufacturing Issues Live Webinar – 26 September 2014
Thank you & Questions
20
MPT Manufacturing Issues
Live Webinar – 26 September 2014
Robert Russell
President and CEO RJR Consulting
Scale-Up Post-Approval
Changes (SUPAC) with FDA
MPT Manufacturing Issues Live Webinar – 26 September 2014
Scale-Up and Post-Approval
Changes (SUPAC)
Initial batch sizes to supply early Phase trials are small and are increased for trial size and commercial production.
This increase is called “scale up”.
These scale-up changes made after drug product approval in components, composition, manufacturing process, manufacturing equipment and/or manufacturing site are SUPAC.
SUPAC guidelines are published by FDA and are based on dosage type form.
MPT Manufacturing Issues Live Webinar – 26 September 2014
FDA Published Guidelines Include:
SUPAC-IR: Immediate Release Solid Oral Dosage Forms: Scale Up and Post-
Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation
SUPAC-IR: Questions and Answers about SUPAC-IR Guidance
SUPAC-MR: Modified Release Solid Oral Dosage Forms: Scale Up and Post-
Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution
Testing, and In Vivo Bioequivalence Documentation
SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral Dosage Forms
Manufacturing Equipment Addendum
SUPAC-SS: Non-sterile Semisolid Dosage Forms: Scale Up and Post-Approval
Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and
In Vivo Bioequivalence Documentation
SUPAC-SS: Non-sterile Semisolid Dosage Forms Manufacturing Equipment
Addendum
Tables provided at the end of all guidance documents that list the change
type, level, documentation and filing type for easy reference (example on next
slide)
MPT Manufacturing Issues Live Webinar – 26 September 2014
MPT Manufacturing Issues
Live Webinar – 26 September 2014
SUPAC-IR, SUPAC-MR and
SUPAC-SS Change Types
MPT Manufacturing Issues Live Webinar – 26 September 2014
Level of Changes for Components
and Composition Components and composition changes are focused on the changes of
excipients in a drug product and not in the change of the amount of drug substance.
Three levels:
Minor (Level 1 change)
Changes that are unlikely to have an impact on formulation quality and performance ex. Change in color or flavor
Changes filed in the annual report (including long term stability)
Moderate (Level 2 change)
Changes that could have a significant impact on the formulation quality and performance ex. Change in technical grade of an excipient
o Tests and filing requirements vary based on therapeutic range, solubility and permeability
Changes filed as a prior approval supplement (all info including accelerated data and in the annual report (long term stability data)
MPT Manufacturing Issues Live Webinar – 26 September 2014
Level of Changes for Components
and Composition Cont’d Major (Level 3 change)
Changes that will likely have a significant impact on formulation quality and performance ex. A qualitative or quantitative excipient change to a narrow therapeutic drug
o Tests and filing requirements vary based on therapeutic range, solubility and permeability
Changes filed as a prior approval supplement (all info including accelerated data and in the annual report (long term stability data)
Preservative change (4th option) only for SUPAC-SS
Any change in the preservative of a semisolid product that may affect the quality of the product
No in vitro release or in vivo bioequivalence needed for preservative changes
o Level 1 – quantitatively 10% or less change in approved amount of preservative
o Level 2 - quantitatively 10% - 20% change in approved amount of preservative
o Level 3 - quantitatively more than 20% in approved amount of preservative
See guidance for any additional chemistry documentation for a preservative change and filing type
MPT Manufacturing Issues Live Webinar – 26 September 2014
Level of Changes for Site Changes
Site changes include changes in location of the site of manufacturer for both
company owned facilities or contract manufacturers.
Does not include scale-up
Three levels:
Minor (Level 1 change)
Site change in a single facility where the same equipment, SOP’s,
environment conditions and controls, and the same personnel are used. No
additional changes are made to the batch records except for admin
information and location of the facility.
Changes filed in the annual report
Moderate (Level 2 change)
Site change with in a contiguous campus or between facilities in adjacent
blocks where the same equipment, SOP’s, environment conditions and
controls, and the same personnel are used. No additional changes are
made to the batch records except for admin information and location of
the facility.
Changes filed as changes being effected supplement and in the annual
report (long term stability data)
MPT Manufacturing Issues Live Webinar – 26 September 2014
Level Changes for Site Changes
Cont’d Major (Level 3 change)
Site change to a different campus where the same equipment,
SOP’s, environment conditions and controls, and the same
personnel are used. No additional changes are made to the
batch records except for admin information and location of
the facility.
Changes filed as changes being effected supplement and in
the annual report (long term stability data)
MPT Manufacturing Issues Live Webinar – 26 September 2014
Level Changes in Batch Size
Includes post approval changes of the batch size from pilot scale to full scale
A scale down is possible, but cannot be scaled down below 100,000 dosage units.
All scale-up changes must be validated and if needed, inspected by appropriate agency personnel
Two levels:
Minor (Level 1 change)
Change in batch size up to 10x the size of pilot batch where the equipment used to produce the test batches is the same design and operating principles and the batches are manufacturing in full compliance with cGMP’s. Additionally the same SOP’s and controls as well as the same formulation and manufacturing procedures are used on the test and full scale product batches
Changes filed in the annual report (including long term stability)
Moderate (Level 2 change)
Change in batch size greater than 10x the size of pilot batch where the equipment used for the test batches is of the same design and operating principles and the batches are in full compliance with cGMP’s
o The same SOP’s and controls, formulation and manufacturing procedures are used on the test and full scale product batches
Changes filed in a changes being effected supplement and in the annual report ( long term stability)
MPT Manufacturing Issues Live Webinar – 26 September 2014
Level Changes in Manufacturing
Manufacturing changes can effect both equipment and the actual
process
Equipment change has two levels:
Minor (level 1 change) - Equipment can be a change from non-
automated to automated or vice versa to move ingredients or a
change to alternative equipment of same design and the
operating principles of the same or of a different capacity
Changes filed in the annual report (including long term stability)
Moderate (Level 2 changes) – change in equipment to a different
design or different operating principles or a change in type of
mixing equipment
Changes filed as prior approval supplement with justification for
change and in the annual report (long term stability data)
MPT Manufacturing Issues Live Webinar – 26 September 2014
Level Changes in Manufacturing
Cont’d Process change has three levels:
Level 1 – Process changes like mixing times and operating speeds
within application/validation ranges
Changes filed in the annual report
Level 2 – Process changes like mixing times and operating speeds
outside of application/validation ranges
Changes filed as changes being effected supplement and in
the annual report (long term stability data)
Level 3 – Change in the type of process used in the manufacture
of the product, such as a change from wet granulation to direct
compression of dry powder
Changes filed in a prior approval supplement with justification
and as the annual report (long term stability)
MPT Manufacturing Issues Live Webinar – 26 September 2014
SUPAC-IR/MR
To be used in conjunction with SUPAC-IR and SUPAC-MR to
determine which documentation should be submitted to FDA when
there is a change in equipment
Only covers manufacturing equipment
Subsections include:
o Particle size reduction/separation
o Blending and mixing
o Granulation
o Drying
o Unit dosing
o Soft gelatin capsules
o Coating/printing/drilling
MPT Manufacturing Issues Live Webinar – 26 September 2014
SUPAC-SS Manufacturing
Equipment Addendum To be used in conjunction with SUPAC-SS to determine which
documentation should be submitted to FDA when there is a change
in equipment
Only covers manufacturing equipment
Subsections include:
o Particle size reduction/separation
o Mixing
o Emulsification
o Deaeration
o Transfer
o Packaging
MPT Manufacturing Issues
Live Webinar – 26 September 2014
SUPAC-IR, SUPAC-MR and
SUPAC-SS Documentation
Required
MPT Manufacturing Issues Live Webinar – 26 September 2014
SUPAC-IR, SUPAC-MR, and
SUPAC-SS Have the same template and same levels of change per topic
Stability and dissolution document requirements are the main things that varies between SUPAC-IR and SUPAC-MR
SUPAC-SS has an in vitro release document instead of a dissolution document
Recommendation are provided for all changes relating to: Component or composition Manufacturing site
Scale up or scale down of manufacture Manufacturing process and equipment
Guidance defines the: Levels of change Recommended chemistry, manufacturing and controls for each level
of change In vitro dissolution test and/or in vivo bioequivalence tests for each
change Documentation needed to support the change
MPT Manufacturing Issues Live Webinar – 26 September 2014
Documentation Required
Includes:
Chemistry document for SUPAC-IR, SUPAC-MR and SUPAC-SS:
Must always follow application/compendial release requirements and
batch records
Additional requirements based on level and type of change include:
o 1 batch long term stability testing
o 1 batch with 3 months accelerated stability reported in the
supplement and 1 batch in long term stability reported in the annual
report
o For SUPAC-IR or SUPAC-SS level 2 or 3 change as required by change
type:
o Significant body of information available: 1 batch with 3 months
accelerated stability reported in the supplement and 1 batch in
long term stability reported in the annual report
o Significant body of information not available: up to 3 batches with
3 months accelerated stability reported in the supplement and 1
batch in long term stability reported in the annual report
MPT Manufacturing Issues Live Webinar – 26 September 2014
Documentation Cont’d
o For SUPAC-MR level 2 or 3 change as required by change type:
o Non-narrow therapeutic range drugs: One batch with three
months’ accelerated stability data reported in prior approval
supplement and long-term stability data of first production batch
reported in annual report.
o Narrow therapeutic range drugs: Three batches with three months’
accelerated stability data reported in prior approval supplement
and long-term stability data of first three production batches
reported in annual report.
o Location of new site and updated batch records
o Notification of change and submission of updated batch records
o Stability must be on production batches for SUPAC-MR
MPT Manufacturing Issues Live Webinar – 26 September 2014
Documentation Required Cont’d
Dissolution Documentation for SUPAC-IR: Must always follow application/compendial
requirements (pharmacopeia for general dissolution specifications)
Additional requirements based on case can be required based on level 2 or 3 change o Case A: High Permeability, High Solubility Drugs
o Dissolution of 85% in 15 minutes in 900 mL of 0.1N HCl. If a drug product fails to meet this criterion, the applicant should perform the tests described for Case B or C
o Case B: Low Permeability, High Solubility Drugs o Multi-point dissolution profile should be performed in
the application/compendial medium at 15, 30, 45, 60 and 120 minutes or until an asymptote is reached. The dissolution profile of the proposed and currently used product formulations should be similar.
MPT Manufacturing Issues Live Webinar – 26 September 2014
Documentation Required Cont’d o Case C: High Permeability, Low Solubility Drugs
o Multi-point dissolution profiles should be performed in water, 0.1 N HCl, and USP buffer media at pH 4.5, 6.5, and 7.5 (five separate profiles) for the proposed and currently accepted formulations. Adequate sampling should be performed at 15, 30, 45, 60, and 120 minutes until either 90% of drug from the drug product is dissolved or an asymptote is reached. A surfactant may be used, but only with appropriate justification. The dissolution profile of the proposed and currently used product formulations should be similar
Dissolution documentation for SUPAC-MR beyond compendial requirements can be:
Nonnarrow therapeutic range drugs (SUPAC-MR level 2 change):
Extended release: multipoint dissolution profiles should be obtained in three other media, for example, in water, 0.1N HCl, and USP buffer media at pH 4.5, and 6.8 for the changed drug product and the biobatch or marketed batch (unchanged drug product). Adequate sampling should be performed, for example, at 1, 2, and 4 hours and every two hours thereafter until either 80% of the drug from the drug product is released or an asymptote is reached. A surfactant may be used with appropriate justification.
MPT Manufacturing Issues Live Webinar – 26 September 2014
Documentation Required Cont’d Delayed release: dissolution tests should be performed in 0.1 N HCl for 2
hours (acid stage) followed by testing in USP buffer media, in the range of
pH 4.5-7.5 (buffer stage) under standard (application/compendial) test
conditions and two additional agitation speeds using the application/
compendial test apparatus (three additional test conditions). If the
application/compendial test apparatus is the rotating basket method
(Apparatus 1), a rotation speed of 50, 100, and 150 rpm may be used, and if
the application/compendial test apparatus is the rotating paddle method
(Apparatus 2), a rotation speed of 50, 75, and 100 rpm may be used.
Multipoint dissolution profiles should be obtained during the buffer stage of
testing. Adequate sampling should be performed, for example, at 15, 30, 45,
60, and 120 minutes (following the time from which the dosage form is
placed in the buffer) until either 80% of the drug from the drug product is
released or an asymptote is reached. The above dissolution testing should
be performed using the changed drug product and the biobatch or
marketed batch (unchanged drug product).
MPT Manufacturing Issues Live Webinar – 26 September 2014
Documentation Required Cont’d All modified release solid oral dosage forms: In the presence of an established in
vitro/in vivo correlation (6), only application/compendial dissolution testing need be performed (i.e., only in vitro release data by the correlating method need to be submitted). The dissolution profiles of the changed drug product and the bio-batch or marketed batch (unchanged drug product) should be similar. The sponsor should apply appropriate statistical testing with justifications (e.g., the f equation) for comparing 2 dissolution profiles (5). Similarity testing for the two dissolution profiles (i.e., for the unchanged drug product and the changed drug product) obtained in each individual medium is appropriate.
Narrow therapeutic range drugs (SUPAC-MR level 3 change):
Extended release: In addition to application/compendial release requirements, a multipoint dissolution profile should be obtained in application/compendial medium for the changed drug product and the bio-batch or marketed batch (unchanged drug product). Adequate sampling should be performed, for example at 1, 2, and 4 hours and every two hours thereafter until either 80% of the drug from the drug product is released or an asymptote is reached.
Delayed release: In addition to application/compendial release requirements, a multipoint dissolution profile should be obtained during the buffer stage of testing using the application/compendial medium for the changed drug product and the bio-batch or marketed batch (unchanged drug product). Adequate sampling should be performed, for example, at 15, 30, 45, 60, and 120 minutes (following the time from which the dosage form is placed in the buffer) until either 80% of the drug from the drug product is released or an asymptote is reached.
MPT Manufacturing Issues Live Webinar – 26 September 2014
Documentation Cont’d
In Vivo Bioequivalence document (SUPAC-IR, SUPAC-MR and
SUPAC-SS):
Not required unless stipulated based on level and type of
change
Level 3 change can require bioequivalence studies
Full BE study for SUPAC-IR or SUPAC-SS
Single dose BE study for SUPAC-MR
o The BE may be waived for both if a suitable in vivo / in
vitro correlation has been verified
MPT Manufacturing Issues Live Webinar – 26 September 2014
SUPAC-SS Documentation
SUPAC-SS requires In vitro release documentation instead of the dissolution
documentation that is required for SUPAC-IR and SUPAC-MR
In vitro tests are used to assure product quality and performance are
maintained over time and in the presence of change as well as assure
consistent delivery of the active component from semisolid products
In vitro release is not required for level 1 changes
Level 2 and 3 changes require:
Components and composition or batch size level 2 change - The in
vitro release rate of a lot of the new/modified formulation or scale-up
batch should be compared with that of a recent lot of comparable
age of the pre-change formulation of the product. The median in vitro
release rates (as estimated by the estimated slope from each cell, see
section VII) of the two formulations should be demonstrated to be
within acceptable limits using the testing procedure described in
section VII of the guidance.
MPT Manufacturing Issues Live Webinar – 26 September 2014
SUPAC-SS Documentation Cont’d
Components and Composition level 3 change - The in vitro release rate of
the new/modified formulation should be established as a point of reference.
Under this level 3 change, in vitro release documentation is not required, but
sponsors are encouraged to develop this information for use in subsequent
changes under this guidance
Equipment or process level 2 change - The in vitro release rate of a lot of the
dosage form prepared in new equipment should be compared with the
release rate of a recent lot of comparable age of the product prepared
using original equipment. The median in vitro release rates (as estimated by
the estimated slope from each cell, see section VII) of the two formulations
should be demonstrated to be within acceptable limits, using the testing
procedure described in section VII (IN VITRO RELEASE TEST)
Manufacturing site level 2 change - The in vitro release rate of a lot of the
dosage form prepared in a new manufacturing site should be compared
with the release rate of a recent lot of comparable age of the product
prepared at the prior site. The median in vitro release rates (as estimated by
the estimated slope from each cell, see section VII) from the two sites should
be demonstrated to be within acceptable limits, using the testing
procedure described in section VII (IN VITRO RELEASE TEST)
MPT Manufacturing Issues Live Webinar – 26 September 2014
Manufacturer Responsibilities
Required to inform FDA of any changes made that fall under any of the SUPAC guidance's
Based on the type of change, it may either be implemented first (notification) or may need prior approval
Depending on the change and its level, it must be informed in one of 3 ways: Annual report
Changes being affected supplement
Prior approval supplement
Use the charts at the end of the guidance's for easy reference to determine the requirements
MPT Manufacturing Issues Live Webinar – 26 September 2014
Thank You & Questions
MPT Manufacturing Issues Live Webinar – 26 September 2014
Learn more about MPTs
www.CAMI-Health.org & www.MPTs101.org
MPT Manufacturing Issues Live Webinar – 26 September 2014
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Thank You!